Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

Chronic kidney disease and polyuria are the clinical hallmarks for NPHP1 patients while the main signs and symptoms for children with other NPHP mutations can be manifold. Initial clinical presentation leading to the diagnosis of nephronophthisis (NPH) or NPH-related ciliopathies in the Nephronophthisis Registry. Although in one half of the children with NPHP1, polyuria (54%) or CKD (46%) led to diagnosis, the main signs and symptoms of children without NPHP1 were less specific, including dysmorphic features (11%), failure to thrive (18%), developmental delay (18%), visual impairment (12%), or fetal tachypnoe (10%). However, the latter symptoms presented significantly earlier, mostly within the first year of life, whereas the first signs of urinary-concentrating defects usually did not become obvious before the age of 4–6 years old. COMA, congenital oculomotor apraxia.

Isolated NPH is the typical phenotype of most NPHP1 patients while complex NPH-related ciliopathies are abundant in the nonNPHP1 group. Frequency of clinically defined nephronophthisis (NPH)-related ciliopathies in the Nephronophthisis Registry with respect to the presence/absence of an NPHP1 deletion. Isolated NPH is more frequent in (A) the NPHP1 group than in (B) children without NPHP1. Nevertheless, in 25%, a homozygous NPHP1 deletion led to a neurologic phenotype as well. (C) Axial magnetic resonance image of a child with Joubert syndrome showing the typical cerebellar vermis hypoplasia, resulting in a positive molar tooth sign. (D) Cerebral magnetic resonance image of a child with Meckel–Gruber syndrome (MKS) showing severe brain malformations: occipital encephalocele and massively enlarged cerebrospinal fluid compartments. (E) An x-ray of a postaxial hexadactyly in a child with Bardet–Biedl syndrome (BBS). COACH, cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis; COMA, congenital oculomotor apraxia; MSS, Mainzer–Saldino syndrome.